Spike-timing dependent plasticity (STDP) is a mechanism thought to underlie much of normal learning, as well as recovery from nervous system injury. The ability to manipulate STDP in selected neural circuits, and specifically during certain behaviors, therefore could have vast potential for enhancing normal learning as well as treating a wide variety of neurological disorders. Indeed, previous work has shown that changes consistent with STDP can be produced in normal humans and in patients with spinal cord injury. These studies have paired i) transcranial stimulation of the corticospinal system with ii) peripheral nerve stimulation, both of which stimulate thousands of neurons at each site, inducing plastic changes relatively nonspecifically in large populations of neurons. Recently, the development of technology for brain-computer interfaces has enabled studies in which spikes recorded from a single neuron in an awake subject can be used to trigger intracortical microstimulation (ICMS) at another electrode with delays appropriate for producing STDP. Three studies have suggested that such spike-triggered ICMS (SpTr-ICMS) can alter cortical output, increase connections between neurons, and modify behavior. But in each of these studies SpTr-ICMS has been delivered continuously over days, during which the subject engaged in a wide variety of unrestrained, natural behaviors. The present proposal therefore aims to address the following questions: 1) Can SpTr-ICMS alter neuronal activity and interactions during a specific behavior when the stimulation is delivered during only that one behavior? 2) Does SpTr-ICMS delivered during one behavior alter neuronal activity and interactions during another behavior? And 3) Does SpTr-ICMS delivered during one behavior produce improvement in that behavior without detrimental effects on another behavior? The high risk of the present R21 proposal lies in the possibility that SpTr-ICMS delivered for only a few hours each day during a specific behavior may be insufficient to induce any changes, or that the changes induced may be non-specific. The potentially high payoff lies in the possibility that SpTr-ICMS will provide a new tool for experimental manipulations that probe the nature and limits of neural plasticity. Such progress would open the way for translational development of SpTr-ICMS as new means of enhancing selected aspects of learning, as well as promoting recovery of specific functions after nervous system injury.